Ward H E, Johnson E A, Goodman I J, Birkle D L, Cottrell D J, Azzaro A J
Department of Behavioral Medicine and Psychiatry, West Virginia University, Robert C. Byrd Health Science Center, Morgantown 26506-9223, USA.
Pharmacol Biochem Behav. 1998 May;60(1):209-15. doi: 10.1016/s0091-3057(97)00580-7.
There is growing evidence for a role of extrahypothalamic corticotropin-releasing factor (CRF) in the pathogenesis of anxiety. A modified form of the defensive withdrawal test was used to test the anxiogenic effects of acute administration of intracerebroventricular (1 microg, i.c.v.) CRF in adult male rats. Habituation to the mild stress of daily handling and subcutaneous (s.c.) saline injection over 2-6 weeks abolished the anxiogenic effects of exogenous CRF. At 6 weeks this habituation also resulted in attenuation of baseline withdrawal behavior. CRF receptor binding was significantly decreased in the amygdala of chronically handled animals and may have been responsible for this habituation phenomenon. Comparison of rats treated with the monoamine oxidase (MAO) inhibitor, phenelzine [3 mg/kg, s.c., daily for 2-6 weeks] to the saline-treated groups revealed a failure to habituate to the chronic handling, as the baseline withdrawal (after injection of artificial CSF) by the phenelzine-treated animals was not different from the baseline withdrawal by unhandled rats. In comparison to rats treated chronically with saline, phenelzine treatment enhanced the anxiogenic effect of CRF. In summary, habituation to a mild chronic stress decreased baseline defensive withdrawal. Intraventricular administration of CRF produced an anxiogenic response as measured in the defensive withdrawal test, which was lost through exposure to mild chronic stress. Two or 6 weeks of daily handling and SC saline injection caused a downregulation of CRF receptors in the amygdala, which could account for the behavioral habituation and the loss of CRF-induced defensive withdrawal. Phenelzine treatment concurrent with mild chronic stress prevented habituation and maintained the anxiogenic effect of CRF in spite of the downregulation of CRF receptors in the amygdala.
越来越多的证据表明，下丘脑外促肾上腺皮质激素释放因子（CRF）在焦虑症的发病机制中起作用。采用改良的防御性退缩试验，检测成年雄性大鼠脑室内注射（1微克，脑室内注射）CRF急性给药的致焦虑作用。在2 - 6周内，让大鼠适应每日处理和皮下注射生理盐水的轻度应激，可消除外源性CRF的致焦虑作用。在6周时，这种适应还导致基线退缩行为减弱。长期处理动物的杏仁核中CRF受体结合显著减少，这可能是这种适应现象的原因。将用单胺氧化酶（MAO）抑制剂苯乙肼[3毫克/千克，皮下注射，每日2 - 6周]处理的大鼠与生理盐水处理组进行比较，发现它们未能适应慢性处理，因为苯乙肼处理的动物（注射人工脑脊液后）的基线退缩与未处理大鼠的基线退缩没有差异。与长期用生理盐水处理的大鼠相比，苯乙肼处理增强了CRF的致焦虑作用。总之，适应轻度慢性应激可降低基线防御性退缩。脑室内注射CRF在防御性退缩试验中产生致焦虑反应，而通过暴露于轻度慢性应激可消除该反应。每日处理和皮下注射生理盐水2周或6周会导致杏仁核中CRF受体下调，这可以解释行为适应以及CRF诱导的防御性退缩的丧失。尽管杏仁核中CRF受体下调，但与轻度慢性应激同时进行的苯乙肼处理可防止适应并维持CRF的致焦虑作用。
